1. Field of the Invention
The present invention relates to measuring a medical parameter and more particularly to a non-invasive glucose measurement device.
2. Description of the Prior Art
Non-Invasive (NI) blood glucose level monitoring has been pursued by many academic and industrial institutions. On-market blood glucose measurements, while achieving remarkable advances in accuracy and minimizing blood sample volume, still require blood draw. Many diabetics harbor anxiety and needle phobia to the point of interfering with timely testing. In spite of numerous publications and proposed devices, NI glucose detection devices usable by diabetics have remained elusive. Diabetes is a long term disease with well-known cardiovascular complications as well as damage to many organs such as the eyes, kidneys, and even causing amputations. A successful NI glucose measurement device would enable more frequent monitoring and compliance with medication regimes, and reduce healthcare cost.
There are numerous devices, methods, and publications in the art describing assessment of blood glucose levels. Physiological concentration of blood glucose is in the ˜0.2 to ˜4.5 mg/ml (˜1 to 25 mM) range. Glucose exists in blood and other human body fluids such as saliva, urine, and interstitial fluid (ISF).
The Prior art of glucose measurements is divided into invasive, minimally-invasive, and non-invasive methods. Invasive methods are generally defined as those that require a droplet of blood which is then analyzed in-vitro to determine the glucose concentration. Methods requiring other body fluid, such as ISF, and/or uses less painful methods for fluid extraction, are generally called minimally-invasive. In non-invasive determinations, no blood or ISF is extracted, and the skin is not punctured. For comprehensive review, Khalil [20] provides description of the principles of many of the technologies that have been employed in the pursuit of NI glucose detection.
Numerous methods and devices have been described to take advantage of the interaction of the glucose molecule with the electromagnetic radiation. Light absorption, reflection, polarization and scattering have been exploited [1-5], particularly in the infrared (IR), near IR (NIR), and middle IR (MIR) since several glucose electronic and vibrational modes interact with radiation in these regions [9-17].
A large number of prior art articles describe the measurement of absorption, emission, polarization, scattering, and/or wavelength dependencies of the glucose molecule, seeking correlation to glucose concentration. The construction of a correlation between the measurements with the amount of glucose has received focus in prior art, as interference from and variability of other components can complicate the construction the correlation, chiefly, interference from blood and skin constituents, variability in the concentration of blood analytes, the inhomogeneity of human skin, diet, blood circulation, temperature, and drugs. Therefore, data analyses resort to the application of complex multivariate calibration for correlating of glucose concentration to the measurements [6-8].
My U.S. Pat. No. 5,581,349 describes a Method for Biological Cell and Particulate Analysis. That patent was not concerned with Glucose per se; however, the techniques taught in that patent can be used with the apparatus of the present invention to detect and monitor glucose levels in humans as will be shown.
Other US patents that are concerned with glucose measurement are herein listed:
U.S. Pat. No. 7,333,841 describes a method and device using NIR radiation on skin of a subject, receiving reflected light and calculating the glucose level from a predetermined calibrating equation. A plurality of the calibrating equations that are classified in terms of a skin thickness parameter indicative of a skin thickness parameter was used.
U.S. Pat. No. 6,748,250 describes method and system of analytes measurements by an attenuated total reflection (ATR) infrared spectroscopy method. The system comprises an input module that provides a non-invasive method in measuring analytes in a patient, such as a measurement of the glucose level and other blood analytes. The measurement is shared among a plurality of output devices such as computers, personal digital assistants (PDAs), cellular phones, etc.
U.S. Pat. No. 6,574,490 describes an apparatus and method which include multiple subsystems to improve photometric accuracy and the signal-to-noise ratio, sampling and calibration errors. Subsystems include Fourier Transform IR (FTIR) spectrometer subsystem, a data acquisition subsystem, and a computing subsystem.
U.S. Pat. No. 6,445,938 describes a device and method for non-invasive glucose measurement using Attenuated Total Reflection (ATR) infrared spectroscopy, and compares two specific regions of a measured infrared spectrum to determine the blood glucose.
U.S. Pat. No. 6,424,849 describes a method for determining the blood glucose in which skin surface is irradiated with IR and where reflected light is used for glucose level based on the intensity of the reflected IR beam.
Similarly, U.S. Pat. No. 6,424,848 describes a method of preparing skin surface and determining glucose levels using attenuated total reflection (ATR) infrared spectroscopy.
U.S. Pat. No. 6,061,582 describes method and apparatus using infrared radiation and a signal processing system. The level is determined by: (a) irradiating a portion of the test subject with near infrared radiation; (b) collecting data concerning the irradiated light on the test subject; (c) digitally filtering the collected data to isolate a portion of the data indicative of the physiological chemical; and (d) determining the amount of physiological chemical in the test subject by applying a defined mathematical model to the digitally filtered data. The collected data is in the form of either an absorbance spectrum or an interferogram.
U.S. Pat. No. 6,043,492 describes a non-invasive blood glucose meter that uses an NIR energy analyzer which includes a light filter assembly of two Fabry-Perot interferometers and a photosensor. A single crystal silicon elastic power source is used to provide the driving power of the Fabry-Perot interferometer to avoid mechanical hysteresis.
U.S. Pat. No. 6,016,435 describes a device for non-invasive determination of a glucose concentration using NIR radiation having successive wavelengths within a range of 1300 nm to 2500 nm, a light projecting unit for projecting the near-infrared radiation on a skin of the subject, a light receiving unit for receiving a resulting radiation emitted from the inside of the skin, and a spectrum analyzer.
U.S. Pat. No. 5,823,966 describes a method and an instrument for a continuous non-invasive detection using remote sensor assembly mounted in subject's ear canal continuously measures analyte concentration by detecting the infrared radiation naturally emitted by a human body using an infrared detector with a combination of adequate filters.
U.S. Pat. No. 5,703,364 describes method and apparatus using NIR with multiple wavelengths, and varying the amount of time that radiation at each wavelength illuminates the subject according to the output level of radiation at each wavelength so as to provide substantially similar detection data resolution for each of the plurality of wavelengths.
U.S. Pat. No. 5,553,613 describes a device for the non-invasive measurement of glucose. The device comprises a solid first portion having a surface profile adapted to be held against the selected body part, a source of near infrared radiation mounted in a second portion associated with said first portion such that near infrared radiation is transmitted through or reflected from said body part, a third portion containing a detector and filters to receive radiation transmitted through or reflected from said body part, to select signals generated by the pulsatile component of the absorption spectrum and to provide a ratio representative of the desired concentration.
U.S. Pat. No. 5,459,317 describes method and apparatus using IR radiation and a signal processing system. The subject is irradiated with NIR and the transmitted or reflected radiation is measured, digitally filtered, and analyzed.
U.S. Pat. No. 5,448,992, also U.S. Pat. No. 5,398,681, describe a method and apparatus based on producing a polarized-modulated laser beam, measuring a phase difference introduced, e.g., by a finger. Phase difference between a reference signal and a probe signal is also measured and data are processed to produce glucose concentration.
U.S. Pat. No. 5,222,496 describes an IR sensor and method using plurality of discrete wavelengths selected from the NIR spectrum, and transmittance or reflectance ratios for various wavelengths are performed.
U.S. Pat. No. 5,070,874 describes non-invasive determination of glucose concentration using radiation in the near infrared over a limited range of wavelengths about 1660 nanometers. The scattered or transmitted radiation is processed to derive an expression of the resulting radiation as a function of the wavelength. Curve derivatives between 1640 and 1670 nanometers are expanded and the glucose concentration is determined from the magnitude, or intensity, of the scattered or transmitted radiation at the maximum or minimum point of the second derivative.
U.S. Pat. No. 4,882,492 describes non-invasive apparatus using both diffuse reflected and transmissive infrared absorption measurements that utilize non-dispersive correlation spectrometry. Spectrally-modified near infrared light from the sample containing the analyte is split into two beams, one of which is directed through a negative correlation filter which blocks light in the absorption bands for the analyte to be measured, and the other of which is directed through a neutral density filter capable of blocking light equally at all wavelengths in the range of interest. Differencing the light intensity between the two light paths provides a measure proportional to analyte concentration.
Glucose solutions are optically active and rotate the polarization plane of linearly polarized light. The rotation angle can be used to measure the glucose concentration. However, depolarization of light occurs because of scattering by skin, and a location that possesses low scattering must be used, e.g., the anterior chamber eye [21, 22]. U.S. Pat. No. 5,009,230, and similarly U.S. Pat. No. 4,901,728, describe devices based upon the effect of glucose in rotating polarized infrared light. In order to compensate for absorption in the tissue, another two orthogonal and equal polarized states of infrared light are used.
Approaches using the techniques of photoacoustics, based on impacting sample with pulsing laser and measuring the acoustic response, have been attempted[18,19]. For example, U.S. Pat. No. 5,119,819 describes a method and apparatus that use acoustic velocity measurements, through the earlobe. The apparatus includes a transducer for transmitting and receiving ultrasonic energy pulses and a reflector for facilitating reflection of the acoustic pulses from the blood. The acoustic velocity is measured to provide a representation of the blood glucose concentration levels.
US published patent application 20050054907 describes a wearable article such as a wristwatch, which include optical and acoustic transducers. A quantum cascade laser is arranged with crystalline acoustic detectors in a photoacoustic effect measurement scheme. Laser pulses stimulate special vibrational states of glucose molecules to produce an acoustic return signal to be received at a piezoelectric detector.
Several approaches using Raman Spectroscopy have been attempted[22]. The method is based on the inelastic scattering from coupling of electronic states with vibrational/rotational modes. Fluorescence and scattering from other components can interfere with Raman signals. Raman and surface-enhanced Raman spectra show less overlap in comparison to e.g., NIR spectroscopy. For example, U.S. Pat. No. 6,424,850 (also, U.S. Pat. No. 6,181,957) describes non-invasive method which detects a Raman spectrum from illuminated aqueous humor with linear or nonlinear multivariate analysis.
U.S. Pat. No. 6,377,828 (also U.S. Pat. No. 6,044,285) describe method and apparatus where the Raman spectra emitted by the tissue are collected and analyzed to determine a concentration of analyte (glucose) present in the tissue.
Fluorescence techniques[25,26] were also used, as in U.S. Pat. No. 6,505,059.
Optical coherence tomography (OCT) [23, 24]: Utilizes light interference/time delay between backscattered light in the sample and reference light in an interferometer. OTC provides higher resolution, but temperature and motion can interference with results. US published patent application 20120116236 describes the use OCT to measure tissue dimensions affected by hydration levels and blood flow variations, which are proposed to increase the accuracy of glucose measurements.
Other techniques include impedance measurements. For example, U.S. Pat. No. 7,050,847 describes a method of measuring impedance of the skin. The measurements are repeated for different depth and at various frequencies. Skin may be exposed to salt solutions.
U.S. Pat. No. 6,841,389, also US published patent application 20100130883, describe methods of total impedance measurement of the skin, which is based on a first order correlation between the glucose concentration and the total impedance.
US published patent application 20110208036 describes a pair of coiled antennas acting as electrodes for dielectric spectroscopy measurements, placing the pair of coiled antenna in signal communication through the media, and scanning for a specific frequency range. Acquiring signals from the coiled antennas during scanning and integrating to determine analyte level.
U.S. Pat. No. 8,043,227 describes a non-invasive system and method for measuring skin hydration from thermal conductivity of the skin with a thermistor for non-invasive measurement of blood analyte detection, such as glucose, with a spectroscopic device having e.g., an infrared source which generates infrared beam and detector for detecting transmitted radiation through portion (e.g., finger) of a subject. The system for detecting blood analyte concentration may include a photoacoustic device or a metabolic heat conformation device.
Prior art techniques used for NI glucose determination show less than satisfactory correlation to glucose concentration. This can be attributed to interference from other cell/tissue components, as the measurements usually sample many components, which may be affected in different manner by variability in glucose concentration. The present invention presents features to isolate the dependency of a particular component on glucose levels, which reduces interference.